Repeated Cocaine Exposure Decreases Dopamine D2-Like Receptor Modulation of Ca2+ Homeostasis in Rat Nucleus Accumbens Neurons

MARIELA F. PÉREZ.; KERSTIN A. FORD , IVAN GOUSSAKOV, GRACE E. STUTZMANN, XIU-TI HU

SYNAPSE

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2010 vol. 65 p. 168 - 180

0887-4476

The nucleus accumbens is a limbic structure in the forebrain which plays a critical rolein cognitive function and addiction. Dopamine modulates activity of medium spinyneurons in the nucleus accumbens. Both dopamine D1-like and D2-like receptors(including D1R or D1,5R, and D2R or D2,3,4R, respectively) are thought to play criticalroles in cocaine addiction. Our previous studies demonstrated that repeated cocaineexposure (which alters dopamine transmission) decreases excitability of nucleusaccumbens medium spiny neurons in cocaine-sensitized, withdrawn rats. Thisdecrease is characterized by a reduction in voltage-sensitive Na+ currents and highvoltage-activated Ca2+ currents, along with increased voltage-gated K+ currents. Thesechanges are associated with enhanced activity in the D1R/cAMP/PKA/proteinphosphatase 1 pathway and diminished calcineurin function. Though D1R-mediatedsignaling is enhanced by repeated cocaine exposure, little is known whether and howthe D2R is implicated in the cocaine-induced nucleus accumbens dysfunction. Here,we performed a combined electrophysiological, biochemical, and neuroimaging studythat reveals the cocaine-induced dysregulation of Ca2+ homeostasis with involvement ofD2R. Our novel findings reveal that D2R stimulation reduced Ca2+ influx preferentiallyvia the L-type Ca2+ channels and evoked intracellular Ca2+ release, likely via inhibitingthe cAMP/PKA cascade, in the nucleus accumbens medium spiny neurons of drug-freerats. However, repeated cocaine exposure abolished the D2R effects on modulatingCa2+ homeostasis with enhanced PKA activity and led to a decrease in whole-cell Ca2+influx. These adaptations, which persisted for 21 days during cocaine abstinence, maycontribute to the mechanism of cocaine withdrawal.